The present invention relates to synthesis of heteroarylamine intermediate compounds.
Aryl- and heteroaryl-substituted ureas have been described as inhibitors of cytokine production. These inhibitors are described as effective therapeutics in cytokine-mediated diseases, including inflammatory and autoimmune diseases. Examples of such compounds are reported in WO 99/23091 and in WO 98/52558.
A key step in the synthesis of these compounds is the formation of the urea bond. Various methods have been reported to accomplish this. For example, as reported in the above references, an aromatic or heteroaromatic amine, II, may be reacted with an aromatic or heteroaromatic isocyanate III to generate the urea IV (Scheme I) 
If not commercially available, one may prepare the isocyanate III by reaction of an aryl or heteroaryl amine Ar2NH2 with phosgene or a phosgene equivalent, such as bis(trichloromethyl) carbonate (triphosgene) (P. Majer and R. S. Randad, J. Org. Chem. 1994, 59, 1937) or trichloromethyl chlorofonmate (diphosgene) (K. Kurita, T. Matsumura and Y. Iwakura, J. Org. Chem. 1976, 41, 2070) to form the isocyanate III, followed by reaction with Ar1NH2 to provide the urea. Other approaches to forming the urea reported in the chemical literature include reaction of a carbamate with an aryl or heteroaryl amine, (see for example B. Thavonekham, Synthesis, 1997, 1189 and T. Patonay et al., Synthetic Communications, 1996, 26, 4253) as shown in Scheme II below for a phenyl carbamate. U.S. patent application Ser. No. 09/611,109 also discloses a process of making heteroaryl ureas by reacting particular carbamate intermediates with the desired arylamine. 
U.S. application Ser. No. 09/505,582 and PCT/US00/03865 describe cytokine inhibiting ureas of formula (I). 
An Ar2NH2 required to prepare preferred compounds described therein is illustrated as formula (A). 
wherein W, Y, and Z are described below.
The synthesis of II, a preferred formula (A) intermediate was described in U.S. application Ser. No. 09/505,582 and PCT/US00/03865 and is illustrated in Scheme III. 
The synthesis begins with a palladium catalyzed carbonylation of 2,5-dibromopyridine (III) to provide ester IV in 55% yield. The reaction is run under pressure (80 psi CO) and must be monitored to minimize formation of the diester, an unwanted by-product. Reduction of IV with diisobutylaluminum hydride at xe2x88x9278xc2x0 C. provides aldehyde V. This is followed by reductive amination to give VI.
Intermediate VI is then converted to II by reaction with t-BuLi at xe2x88x9278xc2x0 C. followed by tributyltin chloride to give tributylstannane VII, followed by palladium catalyzed Stille coupling with intermediate VIII to give II. Conversion of VI and analogous intermediates to other intermediates of formula II via Suzuki coupling is also described in U.S. application Ser. No. 09/505,582 and PCT/US00/03865 (Scheme IV). According to this method, intermediate IX is treated with n-BuLi followed by trimethylborate to give arylboronic acid X. Palladium catalyzed Suzuki coupling with VI provides XI, which is deprotected by treatment with acid to give II. 
This process is not well-suited for large-scale and commercial use for several reasons. One reaction (Scheme III) is run under high pressure (80 psi) and another at extreme temperature (xe2x88x9278xc2x0 C.). The yield of IV is only moderate and by-product formation requires a purification step. These factors, plus the cost of starting materials and reagents make this process too costly for commercial scale.
The preparation of 2-bromo-5-lithiopyridine via reaction of 2,5-dibromopyridine with n-BuLi at xe2x88x92100xc2x0 C. has been described (W. E. Parham and R. M. Piccirilli, J. Org. Chem., 1977, 42, 257). The selective formation of 2-bromo-5-pyridinemagnesium chloride via reaction with 2,5-dibromopyridine with i-PrMgCl at 0xc2x0 C.-rt has also been reported (F. Trecourt et al., Tetrahedron Lett., 1999, 40, 4339). In these cases, the metal-halogen exchange occurred exclusively at the 5 position of the pyridine ring. However, the syntheses of 5-bromo-2-pyridinemagnesium chloride and 5-chloro-2-pyridinemagnesium chloride have not been reported previously.
The preparation of a lithium intermediate 5-chloro-2-lithiopyridine from 2-bromo-5-chloropyridine, has been reported (U. Lehmann et al., Chem., Euro. J., 1999, 5, 854). However, this synthesis requires reaction with n-BuLi at xe2x88x9278xc2x0 C. The preparation of the 5-bromo-2-lithiopyridine from 2,5-dibromopyridine was reported by X. Wang et al. (Tetrahedron Letters, 2000, 4335). However, the method requires cryogenic and high dilution conditions. The selectivity was also dependent on reaction time. It is not suitable for large scale synthesis.
The synthesis of the intermediate 5-bromo-2-iodopyridine by refluxing 2,5-dibromopyridine in HI has been reported (U. Lehmann, ibid). A process using milder conditions for preparing 2-iodopyridine from 2-chloro or 2-bromopyridine has been described (R. C. Corcoran and S. H. Bang, Tetrahedon Lett., 1990, 31, 6757).
It is an object of the invention to provide novel 2-(5-halopyridyl) and 2-(5-halopyrimidinyl) magnesium halides, novel methods of producing them, and to provide a novel method of using said halides in the efficient synthesis of their respective 5-halo-2-substituted pyridines and pyrimidines.
It also an object of the invention to provide a novel method of producing heteroaryl amines of the formula (A) 
wherein Ar, W, Y and Z are described below, the heteroaryl amines are useful in the production of heteroaryl ureas as mentioned above.
This invention relates to a novel strategy for the synthesis of heteroarylamine compounds of the formula (A) which constitute the key component of pharmaceutically active compounds possessing a heteroaryl urea group.
The invention therefore provides for processes of making a compound of the formula (A) 
wherein:
W is CR3 or N, wherein R3 is chosen from hydrogen, C1-5alkyl, C1-5alkoxy, arylC0-5alkyl and xe2x80x94COR4 wherein R4 is chosen from C1-5alkyl, C1-5alkoxy, arylC0-5alkyl and amino which is optionally independently di-substituted by C1-5alkyl, and arylC0-5alkyl; W is preferably CH or N,
Ar is chosen from
phenyl, naphthyl, quinolinyl, isoquinolinyl, tetrahydronaphthyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzimidazolyl, benzofuranyl, dihydrobenzofuranyl, indolinyl, benzothienyl, dihydrobenzothienyl, indanyl, indenyl and indolyl each being optionally substituted by one or more R1 or R2;
Y is chosen from
a bond and a C1-4 saturated or unsaturated branched or unbranched carbon chain optionally partially or fully halogenated, wherein one or more methylene groups are optionally replaced by O, N, or S(O)m and wherein Y is optionally independently substituted with one to two oxo groups, phenyl or one or more C1-4 alkyl optionally substituted by one or more halogen atoms;
wherein when Y is the carbon chain, the left side terminal atom of Y is a carbon (the atom which is covalently attached to the heterocycle possessing W):
Z is chosen from:
aryl, heteroaryl chosen from pyridinyl, piperazinyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, pyrazolyl, triazolyl, furanyl, thienyl and pyranyl and heterocycle chosen from tetrahydropyrimidonyl, cyclohexanonyl, cyclohexanolyl, 2-oxo- or 2-thio-5-aza-bicyclo[2.2.1]heptanyl, pentamethylene sulfidyl, pentamethylene sulfoxidyl, pentamethylene sulfonyl, tetramethylene sulfidyl, tetramethylene sulfoxidyl or tetramethylene sulfonyl, tetrahydropyranyl, tetrahydrofuranyl, 1,3-dioxolanonyl, 1,3-dioxanonyl, 1,4-dioxanyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxidyl, thiomorpholinyl sulfonyl, piperidinyl, piperidinonyl, pyrrolidinyl and dioxolanyl, each of the aforementioned Z are optionally substituted with one to three halogen, C1-6 alkyl, C1-6 alkoxy, C1-3 alkoxy-C1-3 alkyl, C1-6 alkoxycarbonyl, aroyl, C1-3acyl, oxo, pyridinyl-C1-3 alkyl, imidazolyl-C1-3 alkyl, tetrahydrofuranyl-C1-3 alkyl, nitrile-C1-3 alkyl, nitrile, phenyl wherein the phenyl ring is optionally substituted with one to two halogen, C1-6 alkoxy or mono- or di-(C1-3 alkyl)amino, C1-6 alkyl-S(O)m, or phenyl-S(O)m wherein the phenyl ring is optionally substituted with one to two halogen, C1-6 alkoxy, halogen or mono- or di-(C1-3 alkyl)amino;
or Z is optionally substituted with one to three amino or amino-C1-3 alkyl wherein the N atom is optionally independently mono- or di-substituted by amino C1-6alkyl, C1-3alkyl, arylC0-3alkyl, C1-5 alkoxyC1-3 alkyl, C1-5 alkoxy, aroyl, C1-3acyl, C1-3alkyl-S(O)mxe2x80x94 or arylC0-3alkyl-S(O)mxe2x80x94 each of the aforementioned alkyl and aryl attached to the amino group is optionally substituted with one to two halogen, C1-6 alkyl or C1-6 alkoxy;
or Z is optionally substituted with one to three aryl, heterocycle or heteroaryl as hereinabove described in this paragraph each in turn is optionally substituted by halogen, C1-6 alkyl or C1-6 alkoxy;
or Z is nitrile, amino wherein the N atom is optionally independently mono- or di-substituted by C1-6alkyl or C1-3alkoxyC1-3alkyl, C1-6alkyl branched or unbranched, C1-6alkoxy, nitrileC1-4alkyl, C1-6 alkyl-S(O)m, aryl chosen from phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, thienyl and pyranyl each aryl being optionally substituted with one to three halogen, C1-6 alkyl, C1-6 alkoxy, di-(C1-3 alkyl)amino, C1-6 alkyl-S(O)m or nitrile, and phenyl-S(O)m, wherein the phenyl ring is optionally substituted with one to two halogen, C1-6 alkoxy or mono- or di-(C1-3 alkyl)amino;
R1 and R2 are independently chosen from:
a C1-6 branched or unbranched alkyl optionally partially or fully halogenated, acetyl, aroyl, C1-4 branched or unbranched alkoxy, each being optionally partially or fully halogenated, halogen, methoxycarbonyl, C1-3 alkyl-S(O)m optionally partially or fully halogenated, or phenylsulfonyl;
m=0, 1 or 2;
All terms as used herein in this specification, unless otherwise stated, shall be understood in their ordinary meaning as known in the art. For example, xe2x80x9cC1-6alkoxyxe2x80x9d is a C1-6alkyl with a terminal oxygen, such as methoxy, ethoxy, propoxy, pentoxy and hexoxy. All alkyl, alkenyl and alkynyl groups shall be understood as being branched or unbranched where structurally possible and unless otherwise specified. Other more specific definitions are as follows:
Acxe2x80x94acetyl;
DBAxe2x80x94dibenzylideneacetone;
DPPFxe2x80x941,1xe2x80x2-bis(diphenylphosphino)ferrocene;
DPPExe2x80x941,2-bis(diphenylphosphino)ethane;
DPPBxe2x80x941,4-bis(diphenylphosphino)butane;
DPPPxe2x80x941,3-bis(diphenylphosphino)propane;
BINAPxe2x80x942,2xe2x80x2-bis(diphenylphosphino)-1,1xe2x80x2-binaphthyl;
DMExe2x80x94ethylene glycol dimethylether;
DMSOxe2x80x94dimethyl sulfoxide;
DMFxe2x80x94N,N-dimethylformamide;
EtOxe2x80x94ethoxide;
iPrxe2x80x94isopropyl;
tBuxe2x80x94tertbutyl;
THFxe2x80x94tetrahydrofuran;
RT or rtxe2x80x94room temperature;
The term xe2x80x9caroylxe2x80x9d as used in the present specification shall be understood to mean xe2x80x9cbenzoylxe2x80x9d or xe2x80x9cnaphthoylxe2x80x9d.
The term xe2x80x9carylxe2x80x9d as used herein shall be understood to mean aromatic carbocycle, preferably phenyl and naphthyl, or heteroaryl.
The term xe2x80x9cheterocyclexe2x80x9d, unless otherwise noted, refers to a stable nonaromatic 4-8 membered (but preferably, 5 or 6 membered) monocyclic or nonaromatic 8-11 membered bicyclic heterocycle radical which may be either saturated or unsaturated. Each heterocycle consists of carbon atoms and one or more, preferably from 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur. The heterocycle may be attached by any atom of the cycle, which results in the creation of a stable structure. Unless otherwise stated, heterocycles include but are not limited to, for example oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, dioxanyl, tetramethylene sulfonyl, tetramethylene sulfoxidyl, oxazolinyl, thiazolinyl, imidazolinyl, tertrahydropyridinyl, homopiperidinyl, pyrrolinyl, tetrahydropyrimidinyl, decahydroquinolinyl, decahydroisoquinolinyl, thiomorpholinyl, thiazolidinyl, dihydrooxazinyl, dihydropyranyl, oxocanyl, heptacanyl, thioxanyl, dithianyl or 2-oxa- or 2-thia-5-aza-bicyclo[2.2.1]heptanyl.
The term xe2x80x9cheteroarylxe2x80x9d, unless otherwise noted, shall be understood to mean an aromatic 5-8 membered monocyclic or 8-11 membered bicyclic ring containing 1-4 heteroatoms such as N, O and S. Unless otherwise stated, such heteroaryls include: pyridinyl, pyridonyl, quinolinyl, dihydroquinolinyl, tetrahydroquinoyl, isoquinolinyl, tetrahydroisoquinoyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, benzofuranyl, benzothiophenyl, benzpyrazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzooxazolonyl, benzo[1,4]oxazin-3-onyl, benzodioxolyl, benzo[1,3]dioxol-2-onyl, tetrahydrobenzopyranyl, indolyl, indolinyl, indolonyl, indolinonyl, phthalimidyl.
Terms which are analogs of the above cyclic moieties such as aryloxy or heteroaryl amine shall be understood to mean an aryl, heteroaryl, heterocycle as defined above attached to it""s respective functional group.
As used herein, xe2x80x9cnitrogenxe2x80x9d and xe2x80x9csulfurxe2x80x9d include any oxidized form of nitrogen and sulfur and the quaternized form of any basic nitrogen.
The term xe2x80x9chalogenxe2x80x9d as used in the present specification shall be understood to mean bromine, chlorine, fluorine or iodine except as otherwise noted. The compounds made by the novel processes of the invention are only those which are contemplated to be xe2x80x98chemically stablexe2x80x99 as will be appreciated by those skilled in the art. For example, a compound which would have a xe2x80x98dangling valencyxe2x80x99, or a xe2x80x98carbanionxe2x80x99 are not compounds made by processes contemplated by the invention.
In one embodiment of the invention there is provided a process of making the compounds of formula (A) as described hereinabove,
said process comprising:
a) synthesis of a compound of formula (C) from a compound of formula (B) via substitution with an appropriate halide Xc. When Xc is Br, methods known in the art may be utilized.
When Xc is I, the present invention provides a novel process for the substitution of the leaving group (L) with iodide. This was achieved by using the conditions of RxCOCl or (RxCO)2O/metal iodide/solvent/heating (25xc2x0 C.-150xc2x0 C.), wherein Rx is chosen from xe2x80x94C1-7 alkyl, xe2x80x94CF1-3 and xe2x80x94CCl1-3; the metal chosen from Na and K, and the solvent chosen from acetonitrile, acetone, DMSO, DMF and THF. Preferred conditions are AcCl and NaI in acetonitrile at 70-90xc2x0 C. The leaving group L is any suitable leaving group as will be appreciated by those skilled in the art, preferably L is chosen from Cl, Br, xe2x80x94OCORy and xe2x80x94OS(O)mRy, wherein Ry is aryl optionally substituted by C1-4alkyl optionally halogenated, such as tolyl, or Ry is C1-4alkyl optionally halogenated such as CF3 and CCl3, L is more preferably chosen from Br and Cl. 
Xa is chosen from Br and Cl, preferably Br;
Xc is I or Br, preferably I;
Xa is attached via the 4 or 5 ring position, preferably the 5 position.
b) In a one pot process, reacting a compound of the formula (C) with a Grignard reagent Rxe2x80x94Mgxe2x80x94Xb followed by the addition of an Exe2x80x94Yxe2x80x94Z compound wherein Yxe2x80x94Z is as defined above, said Exe2x80x94Yxe2x80x94Z component is further characterized as being an electrophilic derivative of Yxe2x80x94Z and being appropriate for Grignard reagant reactions as will be apparent to the skilled artisan, said reaction taking place in a suitable aprotic solvent at xe2x88x9278xc2x0 C. to RT, preferably 0xc2x0 C. to RT for a reaction time of xc2xd hour to 2 hours, preferably 1 hour, and isolating the compound of the formula (D); 
xe2x80x83wherein:
Xb is chosen from Br, Cl and I;
R is aryl, C1-6alkyl or C5-7cycloalkyl;
As seen in Scheme V below, this one pot novel process step provides for the formation of the Grignard reagant Compound (F): 
where a desirable selective formation was observed. For example the synthesis of 2-(5-halopyridyl)magnesium halides (e.g. 3 and 12) was achieved for the first time.
The process of making compounds of the formula (F) comprises:
reacting a compound of the formula (C) 
xe2x80x83with a magnesium reagent of the formula Rxe2x80x94MgXb; said reaction taking place in a suitable aprotic solvent at xe2x88x9278xc2x0 C. to RT, for a reaction time of xc2xd hour to 2 hours, producing the Grignard compound of the formula (F); and wherein
Xa, is halogen selected from Br and Cl, and Xa is attached via the 4 or 5 ring position;
Xb is halogen chosen from Br, Cl and I;
Xc is I or Br;
W is CR3 or N, wherein R3 is chosen from hydrogen, C1-5alkyl, C1-5alkoxy, arylC0-5alkyl and xe2x80x94COR4 wherein R4 is chosen from C1-5alkyl, C1-5alkoxy, arylC0-5alkyl and amino which is optionally independently or di-substituted by C1-5alkyl, and arylC0-5alkyl; W is preferably CH or N; and
R is aryl, C1-6alkyl or C5-7cycloalkyl.
In a preferred embodiment there is provided a process for making a compound of the formula (F) as described above and wherein
W is CH;
Xa is Br and attached at the 5 ring position;
Xc is I;
the temperature is 0xc2x0 C. to RT; and
the reaction time is 1 hour.
Non-limiting examples of this reaction proceeded with complete selectivity at the 2 position in excellent yield: 
In subsequent steps, the novel process of the invention further comprises:
c) reacting the compound of the formula (D) from step b) with an aryl boronic acid of the formula (E), in the presence of a catalyst chosen from nickel and palladium. Regarding the palladium (Pd) catalyst, non-limiting examples are Pd catalysts chosen from Pd(PPh3)2Cl2, Pd(PPh3)4, PdCl2(DPPE), PdCl2(DPPB), PdCl2(DPPP), PdCl2(DPPF) and Pd/C; or the combination of a palladium source and an appropriate ligand, with the Pd source, for example, being chosen from PdCl2, Pd(OAc)2, Pd2(DBA)3, Pd(DBA)2, and with the ligand being chosen from PPh3, DPPF, DPPP, DPPE, DPPB, P(o-tolyl)3, P(2,4,6-trimethoxyphenyl)3, AsPh3, P(tBu)3, BINAP, and those bound to solid supports that are mimics of the aforementioned ligands, preferably PdCl2 and PPh3. Regarding the nickel (Ni) catalyst, examples of nickel (Ni) catalyst are those chosen from Ni(PPh3)2Cl2, Ni(PPh3)4, NiCl2(DPPE), NiCl2(DPPB), NiCl2(DPPP), NiCl2(DPPF) and Ni/C; or the combination of a Ni source and an appropriate ligand, with the Ni source being NiCl2, and with the ligand being chosen from PPh3, DPPF, DPPP, DPPE, DPPB, P(o-tolyl)3, P(2,4,6-trimethoxyphenyl)3, AsPh3, P(tBu)3, BINAP, and those bound to solid supports that are mimics of the aforementioned ligands. This reaction takes place in a suitable solvent such as ethylene glycol dimethyl ether (DME), THF, toluene, methylene chloride or water, preferably DME, at 0xc2x0 C. to 150xc2x0 C., preferably 25xc2x0 C. to 100xc2x0 C., for a period of 1 to 24 hours preferably about 15 hours, 
 wherein P in the formula (E) is an amino protecting group such as Boc, and subsequently removing said protecting group under suitable conditions to produce a compound of the formula (A).
In a preferred embodiment of the invention there is provided a novel process of making compounds of the formula (A) as described above and wherein:
W is CH;
Ar is chosen from naphthyl, quinolinyl, isoquinolinyl, tetrahydronaphthyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indanyl, indenyl and indolyl each being optionally substituted by one or more R1 or R2 groups;
Y is chosen from:
a bond and
a C1-4 saturated or unsaturated carbon chain wherein one of the carbon atoms is optionally replaced by O, N, or S(O)m and wherein Y is optionally independently substituted with one to two oxo groups, phenyl or one or more C1-4 alkyl optionally substituted by one or more halogen atoms; wherein when Y is the carbon chain, the left side terminal atom of Y is a carbon (the atom which is covalently attached to the heterocycle possessing W):
Z is chosen from:
phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, furanyl, thienyl, dihydrothiazolyl, dihydrothiazolyl sulfoxidyl, pyranyl, pyrrolidinyl which are optionally substituted with one to three nitrile, C1-3 alkyl, C1-3 alkoxy, amino or mono- or di-(C1-3 alkyl)amino;
tetrahydropyranyl, tetrahydrofuranyl, 1,3-dioxolanonyl, 1,3-dioxanonyl, 1,4-dioxanyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxidyl, piperidinyl, piperidinonyl, piperazinyl, tetrahydropyrimidonyl, pentamethylene sulfidyl, pentamethylene sulfoxidyl, pentamethylene sulfonyl, tetramethylene sulfidyl, tetramethylene sulfoxidyl or tetramethylene sulfonyl which are optionally substituted with one to three nitrile, C1-3 alkyl, C1-3 alkoxy, amino or mono- or di-(C1-3 alkyl)amino;
nitrile, C1-6 alkyl-S(O)m, halogen, C1-4 alkoxy, amino, mono- or di-(C1-6 alkyl)amino and di-(C1-3alkyl)aminocarbonyl;
In a more preferred embodiment of the invention there is provided a novel process of making compounds of the formula (A) as described immediately above and wherein:
Ar is naphthyl;
Y is chosen from:
a bond and
a C1-4 saturated carbon chain wherein the left side terminal atom of Y is a carbon (the atom which is covalently attached to the heterocycle possessing W) and one of the other carbon atoms is optionally replaced by O, N or S and wherein Y is optionally independently substituted with an oxo group;
Z is chosen from:
phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, dihydrothiazolyl, dihydrothiazolyl sulfoxide, pyranyl and pyrrolidinyl which are optionally substituted with one to two C1-2 alkyl or C1-2 alkoxy;
tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxidyl, piperidinyl, piperidinonyl, piperazinyl and tetrahydropyrimidonyl which are optionally substituted with one to two C1-2 alkyl or C1-2 alkoxy; and
C1-3 alkoxy;
In yet a more preferred embodiment of the invention there is provided a novel process of making compounds of the formula (A) as described immediately above and wherein:
Ar is 1-naphthyl wherein the NH2 is at the 4 position;
Y is chosen from:
a bond, xe2x80x94CH2xe2x80x94, xe2x80x94CH2CH2xe2x80x94 and xe2x80x94C(O)xe2x80x94,;
In an ultimately preferred embodiment of the invention there is provided a novel process of making compounds of the formula (A) as described immediately above and wherein:
Y is
xe2x80x94CH2xe2x80x94;
Z is morpholinyl;
Formation of the reaction intermediate (E) can be accomplished by first protecting an aryl-amine followed by boronic acid formation through a sequence of metal-bromine exchange, quenching with trialkylborate and hydrolysis, as can be seen in Scheme V in the conversion of 7 to 9. Compounds of the formula (E) possessing other desired Ar can be accomplished without undue experimentation by variations apparent to those of ordinary skill in the art in view of the teachings in this specification and the state of the art.
A desirable novel feature of the process of the invention is the selective formation of a 2-(5-halopyridyl) or 2-(5-halopyrimidinyl) magnesium halides, preferably 2-(5-halopyridyl) magnesium halides (e.g. 3 and 12, vide infra), and their subsequent reactions with the in situ generated Exe2x80x94Yxe2x80x94Z electrophiles. Below in Scheme 1, the addition of 2-(5-halopyridyl) magnesium halide 3 to the immonium salt 6 was carried out without the isolation of the immonium salt.
A non-limiting example for a compound of the formula (A) is the amine 1 shown in Scheme V. 
Reaction intermediate (2) with a generic formula (B) above can be obtained as exemplified in Scheme VI below. Addition of a copper catalyst may be required for transformations involving certain types of electrophiles, for example the alkylation reaction of the Grignard intermediate with various alkyl halides and epoxides. 
Examples of appropriate electrophiles are shown in the table below. Methods of making Yxe2x80x94Z electrophilic derivatives are within the skill in the art. Y component in Yxe2x80x94Z is a derivative of the Y of the formula (A) of the final product upon the addition of the electrophile to the Grignard intermediate. Products may be further derivatized to achieve the desired Yxe2x80x94Z. Such further transformations are within the skills in the art. A non-limiting example is shown below for a preferred embodiment of Z in the formula (A), i.e., the morpholino immonium salt 6. Reference in this regard may be made to Heaney, H.; Papageorgiou, G.; Wilkins, R. F. Tetrahedron 1997, 53, 2941; Sliwa, H.; Blondeau, D. Heterocycles 1981, 16, 2159;. 
In this example, Exe2x80x94Yxe2x80x94Z is compound 6, wherein morpholinyl represents Z and Y is xe2x80x94CH2xe2x80x94 in the final product.
As described above, any electrophile represented by Y, possessing a Z component and compatible with Grignard type reactions are contemplated to be within the scope of the invention. Additional non-limiting examples of Exe2x80x94Yxe2x80x94Z are:
and wherein for the formula (A):
Y is xe2x80x94CH2xe2x80x94; and
Z is chosen from:
heterocycle chosen from morpholinyl, thiomorpholinyl, piperidinyl and pyrrolidinyl each of the aforementioned Z are optionally substituted with one to three halogen, C1-6 alkyl, C1-6 alkoxy, C1-3 alkoxy-C1-3 alkyl, C1-6 alkoxycarbonyl, aroyl, C1-3acyl, oxo, pyridinyl-C1-3 alkyl, imidazolyl-C1-3 alkyl, tetrahydrofuranyl-C1-3 alkyl, nitrile-C1-3 alkyl, nitrile, phenyl wherein the phenyl ring is optionally substituted with one to two halogen, C1-6 alkoxy, di-(C1-3 alkyl)amino, C1-6 alkyl-S(O)m, or phenyl-S(O)m wherein the phenyl ring is optionally substituted with one to two halogen, C1-6 alkoxy or di-(C1-3 alkyl)amino;
or Z is optionally substituted with one to three one to three amino or amino-C1-3 alkyl wherein the N atom is optionally independently di-substituted by aminoC1-6alkyl, C1-3alkyl, arylC0-3alkyl, C1-5 alkoxy C1-3 alkyl, C1-5 alkoxy, aroyl, C1-3acyl, C1-3alkyl-S(O)mxe2x80x94 or arylC0-3alkyl-S(O)mxe2x80x94 each of the aforementioned alkyl and aryl attached to the amino group is optionally substituted with one to two halogen, C1-6 alkyl or C1-6 alkoxy; or Z is optionally substituted with one to three aryl or heterocycle as hereinabove described in this paragraph each in turn is optionally substituted by halogen, C1-6 alkyl or C1-6 alkoxy;
or Z is amino wherein the N atom is optionally independently mono- or di-substituted by C1-6alkyl or C1-3alkoxy C1-3alkyl, C1-6alkyl branched or unbranched, C1-6alkoxy, nitrileC1-4alkyl, C1-6 alkyl-S(O)m, aryl chosen from phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, thienyl and pyranyl each aryl being optionally substituted with one to three halogen, C1-6 alkyl, Cl-6 alkoxy, di-(C1-3 alkyl)amino, C1-6 alkyl-S(O)m or nitrile, and phenyl-S(O)m, wherein the phenyl ring is optionally substituted with one to two halogen, C1-6 alkoxy or mono- or di-(C1-3 alkyl)amino;
said reaction comprising:
reacting a compound of the formula (C) 
xe2x80x83with a magnesium reagent of the formula Rxe2x80x94MgXb; said reaction taking place in a suitable aprotic solvent at xe2x88x9278xc2x0 C. to RT, for a reaction time of xc2xd hour to 2 hours producing the Grignard compound (F): 
wherein
Xa, is halogen selected from Br and Cl, and Xa is attached to the ring via the 4 or 5 position;
Xb is halogen chosen from Br, Cl and I;
Xc is I or Br;
W is CH, CCH3 or N; and
R is aryl, C1-6alkyl or C5-7cycloalkyl;
subsequently reacting the Grignard compound from the prior step with a N,N-dialkylformamide such as DMF to form an aldehyde: 
xe2x80x83and isolating the aldehyde;
reacting the aldehyde with an appropriate Z group under nucleophilic addition conditions to provide the compound (D) 
xe2x80x83This transformation is within the skill in the art and involves reacting of the aldehyde and the appropriate Z component under acidic conditions such as HCl, AcOH, H2SO4 etc, preferably AcOH, in a suitable solvent such as THF, methylene chloride, 1,2-dichloroethane, preferably 1,2-dichloroethane for 0.5-5 h (preferably 2 h) at about RT followed by in situ reduction for 0.5-5 h (preferably 2 h) to provide the product (D).
Subsequent addition of the NH2xe2x80x94Ar compound can be done as described hereinabove, to provide the final product compound of the formula (A) as described above in this embodiment of the invention. A non-limiting example of this embodiment of the invention is shown in Scheme VII. 
In order that this invention be more fully understood, the following examples are set forth. These examples are for the purpose of illustrating preferred embodiments of this invention, and are not to be construed as limiting the scope of the invention in any way.